The present invention relates to a method for imparting pharmacological activities to immunoglobulin such as eosinophilia-suppressive action, immunomodulating action, therapeutic action for autoimmune disease, antiinflammatory action, antiallergic action, etc. which are not inherent to naturally occurring immunoglobulin. The present invention also relates to activated immunoglobulin obtained by said method and to pharmaceutical compositions containing said activated immunoglobulin.
When a foreign substance invades a living organism, various reactions take place in the organism for removing the foreign substance. One of the reactions is the immune reaction whereby a specific protein (antibody) corresponding to the foreign substance (antigen) is produced. The immune reaction is a vital reaction for defending the organism against the invasion of foreign substances such as pathogens and various other proteins, polysaccharides, etc. The nature of the immune reaction is based upon an antigen-antibody reaction in which antibody is bonded to antigen in a specific manner.
The main activity of an antibody is a binding activity which is specific to an antigen. When an antigen is in the form of particles such as bacteria, an agglutination reaction due to the formation of cross-linking of the antibody among the particles is induced. When an antigen has toxicity, enzymatic activity, etc., a neutralization reaction due to binding of the antibody or a hemolytic reaction, bacteriolytic reaction, immune adherence reaction, immunophagocytosis, etc. due to activation by binding of an antigen-antibody complex with complement components in the blood are induced. These reactions constitute immune response reactions in a living organism against the invasion of a foreign substance.
Immunoglobulin is a generic name for antibody proteins and proteins which are similar to the antibody proteins in terms of structures and functions. Immunoglobulin is classified into five classes depending upon the properties of the proteins. For example, IgG (immunoglobulin G) is a main component of immunoglobulin. IgG is the highest in terms of both production amount and blood level, is produced continuously, and has a long half life in blood. Therefore, it has been recognized as an antibody component which is important for maintaining continuous immunity. On the other hand, IgM (immunoglobulin M) is produced in an early stage, even by stimulation from an antigen in a small amount. However, its production is low and transient. Also, it is believed to be an antibody which plays a leading role in early protection. With respect to IgA (immunoglobulin A) it is predominantly present in external secretions such as milk, tears, saliva, and mucous or secretions from digestive organs, genitourinary, and respiratory tracts. IgA is considered to play a main role for the direct protection against infection from the outside through the respiratory tracts and the mouth.
Based upon the antibody activity which is inherent to immunoglobulin as mentioned above, immunoglobulin preparations prepared from human serum have been used as pharmaceuticals. Preparations solely consisting of immunoglobulin of the natural type prepared by mere purification and concentration of serum contain various antibodies against pathogens of various infectious diseases and products thereof. Accordingly, they may be used for prevention and improvement in symptoms of not only non- or hypoglobulinemia but also viral diseases such as measles, hepatitis (type A) and poliomyelitis. Additionally, the immunoglobulin preparations are used together with antibiotics. There are also preparations of immunoglobulin of the natural type which are prepared from special serum which are used for special diseases such as tetanus and hepatitis B.
In order to make the intravenous injection of immunoglobulin of the natural type possible, enzymatic and chemical treatments and modifications are applied to the natural immunoglobulin. An object of the treatment is the removal of agglutinated globulin molecules which are the cause of shock-like symptoms. For example, preparations where the immunoglobulin is treated with pepsin, plasmin, polyethylene glycol, or an ion exchange resin, or treated at pH 4 and those in which immunoglobulin is alkylated or sulfonated are available. Like the preparations of immunoglobulin of the natural type, the pharmacological action of these preparations of the processed type are also based upon the antibody action which is inherent to immunoglobulin.
Thus, the immunoglobulin preparations which are used at present are expected to provide the therapeutic effect due to the above-mentioned physiological activity inherent to the naturally occurring immunoglobulin antibody. There has been no report wherein globulin of the natural type is processed to provide a new pharmacological activity.
The present invention provides a method of activating immunoglobulin to obtain pharmacological activity such as eosinophilia-suppressive action, immunomodulating action, therapeutic action for autoimmune disease, antiinflammatory action or antiallergic action, which is not inherently available in immunoglobulin of the natural type. The present invention also provides activated immunoglobulin and pharmaceutical compositions containing pharmaceutically effective amounts of said activated immunoglobulin which exhibit eosinophilia-suppressive action, immunomodulating action, therapeutic action for autoimmune disease, antiinflammatory action, or antiallergic action.
The activated immunoglobulin of the present invention exhibits pharmacological activity which is not exhibited by the natural or original immunoglobulin from which the activated immunoglobulin is obtained. For example, eosinophilia-suppressive action, immunomodulating action, therapeutic action for autoimmune disease, antiinflammatory action, and anti-allergic action is exhibited by the activated immunoglobulin of the present invention. Unexpectedly superior promoting action toward IgM and IgG antibody production and excellent suppressive action to delayed type hypersensitivity (DTH) is exhibited by the activated immunoglobulin. Also, substantial inhibition of eosinophil exudation is exhibited by the activated immunoglobulin but is not exhibited by the natural or non-activated immunoglobulin. The activated immunoglobulin of the present invention also exhibits substantial suppression of the clinical symptoms resulting from the onset of experimental allergic encephalomyelitis (EAE) which is not exhibited by the natural or non-activated immunoglobulin.
The activated immunoglobulin may be prepared by admixing immunoglobulin with a histamine component and then removing the histamine component to activate the immunoglobulin. In embodiments of the present invention, the weight ratio of the histamine component admixed with the immunoglobulin may range from 0.015 to 150 xcexcg, preferably from 0.075 to 75 xcexcg of the histamine component (based upon the amount of histamine) to 1 gram of immunoglobulin. Removal of at least a substantial portion of the histamine component may be performed by dialysis, gel filtration, adsorption chromatography, ion exchange chromatography, or affinity chromatography.
The activated immunoglobulin of the present invention and pharmaceutical compositions containing pharmaceutically effective amounts of the activated immunoglobulin may be used for the treatment of autoimmune diseases such as chronic rheumatoid arthritis, systemic lupus erythematodes and multiple sclerosis, and immunodeficiency syndromes. Eosinophilia caused by infectious diseases, parasitic diseases, diseases of respiratory organs, autoimmune diseases, malignant tumors, etc. may also be treated with the activated immunoglobulin and pharmaceutical compositions of the present invention. The activated immunoglobulin and pharmaceuticals containing it may be also used to treat allergic diseases such as bronchial asthma, allergic rhinitis, vasomotor rhinitis, urticaria, chronic eczema and atopic dermatitis.